In the last two decades, scientific methodologies for the prediction of the design, performance and classification of fragrance mixtures have been developed at the Laboratory of Separation and ...Reaction Engineering. This review intends to give an overview of such developments. It all started with the question: what do we smell? The Perfumery Ternary Diagram enables us to determine the dominant odor for each perfume composition. Evaporation and 1D diffusion model is analyzed based on vapor-liquid equilibrium and Fick’s law for diffusion giving access to perfume performance parameters. The effect of matrix and skin is addressed and the trail of perfumes analyzed. Classification of perfumes with the perfumery radar is discussed. The methodology is extended to flavor and taste engineering. Finally, future research directions are suggested.
•This publication is designed to update the RIFM safety assessment process, which follows a series of decision trees.•This process incorporates advances in approaches in risk assessment used by RIFM ...over the past ten years.•A framework for choosing structural analogs and consideration of the Threshold of Toxicological Concern (TTC) are included.•Quantitative Risk Assessment (QRA) for dermal sensitization and aggregate exposure assessment methodologies are included.•The latest alternatives to animal testing methodology and environmental risk assessment are included.
The Research Institute for Fragrance Materials, Inc. (RIFM) has been engaged in the generation and evaluation of safety data for fragrance materials since its inception over 45 years ago. Over time, RIFM's approach to gathering data, estimating exposure and assessing safety has evolved as the tools for risk assessment evolved. This publication is designed to update the RIFM safety assessment process, which follows a series of decision trees, reflecting advances in approaches in risk assessment and new and classical toxicological methodologies employed by RIFM over the past ten years. These changes include incorporating 1) new scientific information including a framework for choosing structural analogs, 2) consideration of the Threshold of Toxicological Concern (TTC), 3) the Quantitative Risk Assessment (QRA) for dermal sensitization, 4) the respiratory route of exposure, 5) aggregate exposure assessment methodology, 6) the latest methodology and approaches to risk assessments, 7) the latest alternatives to animal testing methodology and 8) environmental risk assessment. The assessment begins with a thorough analysis of existing data followed by in silico analysis, identification of ‘read across’ analogs, generation of additional data through in vitro testing as well as consideration of the TTC approach. If necessary, risk management may be considered.
•2-Pentylcyclopentan-1-one; a safety assessment based on RIFM's criteria.•A safety assessment based on 7 human health endpoints plus environmental.•All endpoints were cleared using target data, ...read-across, and/or TTC.
•α-Methylbenzyl isobutyrate; a safety assessment based on RIFM's criteria.•A safety assessment based on 7 human health endpoints plus environmental.•All endpoints were cleared using target data, ...read-across, and/or TTC.
•Assignment of Cramer class plays a significant role in setting the TTC value.•The assignment of 1016 fragrance materials by 3 different approaches was compared.•Two in silico programs differed in ...16% of cases in the Cramer class assigned.•Strategies for assuring the robust assignment of a Cramer class are proposed.
The Threshold of Toxicological Concern (TTC) is a pragmatic approach in risk assessment. In the absence of data, it sets up levels of human exposure that are considered to have no appreciable risk to human health. The Cramer decision tree is used extensively to determine these exposure thresholds by categorizing non-carcinogenic chemicals into three different structural classes. Therefore, assigning an accurate Cramer class to a material is a crucial step to preserve the integrity of the risk assessment. In this study the Cramer class of over 1000 fragrance materials across diverse chemical classes were determined by using Toxtree (TT), the OECD QSAR Toolbox (TB), and expert judgment. Disconcordance was observed between TT and the TB. A total of 165 materials (16%) showed different results from the two programs. The overall concordance for Cramer classification between TT and expert judgment is 83%, while the concordance between the TB and expert judgment is 77%. Amines, lactones and heterocycles have the lowest percent agreement with expert judgment for TT and the TB. For amines, the expert judgment agreement is 45% for TT and 55% for the TB. For heterocycles, the expert judgment agreement is 55% for TT and the TB. For lactones, the expert judgment agreement is 56% for TT and 50% for the TB. Additional analyses were conducted to determine the concordance within various chemical classes. Critical checkpoints in the decision tree are identified. Strategies and guidance on determining the Cramer class for various chemical classes are discussed.
The human repeated insult patch test (HRIPT) has a history of use in the fragrance industry as a component of safety evaluation, exclusively to confirm the absence of skin sensitization at a defined ...dose.
The aim of the study was to document the accumulated experience from more than 30 years of conducting HRIPTs.
A retrospective collation of HRIPT studies carried out to a consistent protocol was undertaken, with each study comprising a minimum of 100 volunteers.
The HRIPT outcomes from 154 studies on 134 substances using 16,512 volunteers were obtained. Most studies confirmed that at the selected induction/challenge dose, sensitization was not induced. In 0.12% of subjects (n = 20), there was induction of allergy. However, in the last 11 years, only 3 (0.03%) of 9854 subjects became sensitized, perhaps because of improved definition of a safe HRIPT dose from the local lymph node assay and other skin sensitization methodologies, as well as more rigorous application of the standard protocol after publication in 2008. This experience with HRIPTs demonstrates that de novo sensitization induction is rare and becoming rarer, but it plays an important role as an indicator that toxicological predictions from nonhuman test methods (in vivo and in vitro methods) can be imperfect.
•13-Methyloxacyclopentadecan-2-one; a safety assessment based on RIFM's criteria.•A safety assessment based on 7 human health endpoints plus environmental.•All endpoints were cleared using target ...data, read-across, and/or TTC.
•Hexyl 2-methylbutyrate; a safety assessment based on RIFM's criteria.•A safety assessment based on 7 human health endpoints plus environmental.•All endpoints were cleared using target data, ...read-across, and/or TTC.
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•The current practice is to use 100% skin absorption default value when experimental data is lacking.•An in silico skin absorption model tailored for fragrances, assigns absorption ...values of 10%, 40%, or 80% based on Jmax.•The model may be used confidently for non-fragrance material provided they meet certain specified criteria.•A hypothetical example on the application of this skin absorption model in the safety assessment is presented.
Fragrance materials are widely used in cosmetics and other consumer products. The Research Institute for Fragrance Materials (RIFM) evaluates the safety of these ingredients and skin absorption is an important parameter in refining systemic exposure. Currently, RIFM's safety assessment process assumes 100% skin absorption when experimental data are lacking. This 100% absorption default is not supportable and alternate default values were proposed. This study aims to develop and validate a practical skin absorption model (SAM) specific for fragrance material. It estimates skin absorption based on the methodology proposed by Kroes et al. SAM uses three default absorption values based on the maximum flux (Jmax) – namely, 10%, 40%, and 80%. Jmax may be calculated by using QSAR models that determine octanol/water partition coefficient (Kow), water solubility (S) and permeability coefficient (Kp). Each of these QSAR models was refined and a semi-quantitative mechanistic model workflow is presented. SAM was validated with a large fragrance-focused data set containing 131 materials. All resulted in predicted values fitting the three-tiered absorption scenario based on Jmax ranges. This conservative SAM may be applied when fragrance material lack skin absorption data.
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